Tele nucleophilic substitutions of hydrogen in m-(Trichloromethyl) nitrobenzenes with cyano and ester carbanions

Article abstract of DOI:10.1002/ejoc.200901303

Stabilized carbanions of malonates, 2-phenylacetonitrile, or isopropyl 2-phenylacetate add to m-(trichloromethyl)nitrobenzene derivatives to form σ^H adducts that lose a chloride ion to give intermediate exo-dichloromethylene nitrocyclohexadienes. These undergo re-aromatization through 1, 5hydrogen shift to yield tele substitution mono adducts. Depending on the stoichiometry of the nitroarene to the carbanion, further addition of the nucleophile to the tele mono adduct can yield a mixture of products that are either double or triple adducts. At low temperature, the σ^H adducts undergo direct 1,2-addition in competition with chloride ion elimination/1,5-hydrogen shift.

Full text of DOI:10.1002/ejoc.200901303

FULL PAPER
DOI: 10.1002/ejoc.200901303
tele Nucleophilic Substitutions of Hydrogen in m-(Trichloromethyl)-
nitrobenzenes with Cyano and Ester Carbanions
Marek Surowiec,[a] Dimitris Belekos,[b] Mieczysław Makosza,*[a] and George Varvounis*[b]
˛
Keywords: Carbanions / Michael addition / Arenes / Nucleophilic substitution / Elimination
Stabilized carbanions of malonates, 2-phenylacetonitrile, or
isopropyl 2-phenylacetate add to m-(trichloromethyl)nitro-
benzene derivatives to form σH adducts that lose a chloride
ion to give intermediate exo-dichloromethylene nitrocy-
clohexadienes. These undergo re-aromatization through 1,5-
pending on the stoichiometry of the nitroarene to the carban-
ion, further addition of the nucleophile to the tele mono ad-
duct can yield a mixture of products that are either double
or triple adducts. At low temperature, the σH adducts un-
dergo direct 1,2-addition in competition with chloride ion eli-
hydrogen shift to yield tele substitution mono adducts. De- mination/1,5-hydrogen shift.
duct is followed by rapid base-induced β-elimination of HL
Introduction
to give the final SNH product.[4] There are two other pos-
sible paths that anionic σH adducts follow to give products.
In both cases, hydrogen atom transfer takes place from the
position of nucleophilic attack to a position occupied pre-
viously by a leaving group. Reactions in which leaving
groups are vicinal or more than one bond length from the
site of nucleophilic addition to the arene are known as cine
or tele substitutions, respectively. A general discussion and
numerous examples of these processes are presented in a
There are two major reactions between nucleophilic
agents and electron-deficient arenes; that is, addition in po-
sitions occupied by leaving groups X such as halogens to
form anionic σX adducts and addition in positions occupied
by hydrogen to form anionic σH adducts. As a rule, forma-
tion of anionic σH adducts proceeds much faster than an-
ionic σX formation. Rapid departure of X– from anionic
σX adducts leads to the well-recognized SNAr reaction,[1]
whereas formation of anionic σH adducts by spontaneous
departure of hydride anions does not proceed. Rapid for-
mation of anionic σH adducts are of interest due to their
conversion into products of nucleophilic substitution of hy-
drogen, SNH. As a result, several methods have been devel-
oped in which anionic σH adducts are converted into prod-
ucts of SNH.[2] The inability of the hydride anion to depart
spontaneously from the anionic σH adducts is prevented by
the addition of an external oxidant. Indeed, oxidation of
anionic σH adducts is the most straightforward way of con-
verting these intermediates into SNH products.[3] Numerous
examples of oxidative nucleophilic substitution of hydrogen
(ONSH) in nitroarenes and other electron-deficient arenes
have been reported.[2,3] An alternative and perhaps the most
general and practically useful variant of SNH is vicarious
nucleophilic substitution (VNS), which proceeds when the
nucleophile contains a leaving group L. Addition of the nu-
cleophile to the arene and formation of the anionic σH ad-
recent review by Suwin´ski and Swierczek.[5] Since the publi-
´
cation of this review, nine papers have reported tele substi-
tution between nucleophiles and electron-deficient arenes.
These arenes are 6-(1,2-dibromo-2-phenylethyl)pteridine-
diones, dichloropyrazines, N-fluoropyridinium fluoride, 2-
(1-chloropropyl)imidazole hydrochlorides, 3-trichloro-
methyl-1,2,4-triazines, [(η6-arene)tricarbonyl]chromium or
tricarbonyl(η5-cyclohexadienyl)manganese complexes, and
halogenomethylnitrobenzenes.[6]
Our work on tele nucleophilic substitution has been fo-
cused on the reaction of 3-(trichloromethyl)pyridines with
O, N, and S nucleophiles; 1-nitro-3- and 1,3-dinitro-5-(tri-
chloromethyl)benzene and 3-(trichloromethyl)benzonitrile
with O and S nucleophiles; and tele versus oxidative substi-
tution of hydrogen in 1-nitro-3-(trichloromethyl)benzene
and 1-(chloro or dichloromethyl)-3-nitrobenzenes with
Grignard reagents.[7]
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22/6326681
Results and Discussion
Continuing our previous work with Grignard rea-
gents,[7d] we now present some results of tele substitution
in 1-nitro-3-(trichloromethyl)benzene (1a) and 1-chloro-4-
nitro-2-(trichloromethyl)benzene (1b) with stabilized carb-
anions derived from diethyl malonate, diethyl 2-methyl-
E-mail: icho-s@ich.edu.pl
[b] Department of Chemistry, Section of Organic Chemistry and
Biochemistry, University of Ioannina,
45110 Ioannina, Greece
Fax: +30-26510/08799
E-mail: gvarvoun@cc.uoi.gr
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M. Surowiec, D. Belekos, M. Makosza, G. Varvounis
˛
FULL PAPER
malonate, di-tert-butyl malonate, diethyl 2-bromomalonate, (Table 1, Entry 2). However, when THF was used as the
phenylacetonitrile, or isopropyl phenylacetate with KOtBu solvent in this reaction, only starting material was reco-
as a base. Reaction of 1a with diethyl malonate (1.5 equiv.) vered. This suggests that the use of DMF as cosolvent sol-
and KOtBu (2.5 equiv.) in THF/DMF at 0 °C under an at- vates the potassium ions, rendering the carbanions more
mosphere of argon gave a mixture of three tele substitution nucleophilic. The reaction of 1a with di-tert-butyl malonate/
products: mono adduct 2a, double adduct 3a, and triple KOtBu gave analogous results. Thus, when 1a was treated
adduct 4a in 23, 17, and 22% yield, respectively. Unreacted with di-tert-butyl malonate (1.5 equiv.) and KOtBu
1a was also recovered in 17% yield (Table 1, Entry 1; (2.5 equiv.) compounds 5, 3b, and 4b were obtained in 26,
Scheme 1). When the reaction was repeated with a smaller 18, and 20% yield, respectively, together with 34% of unre-
ratio of diethyl malonate (3 equiv.) and KOtBu (4 equiv.), acted 1a (Table 1, Entry 3). It is postulated that aldehyde 5
the sole product was 4a, which was obtained in 54% yield is a result of the hydrolysis of 2b during workup. Further-
more, the reaction of 1a with di-tert-butyl malonate
(3 equiv.) and KOtBu (4 equiv.) gave 4b in 48% yield as the
only product (Table 1, Entry 4). The yield of 4b is compar-
Table 1. Nucleophilic reaction of dialkyl malonates with 1a.
Entry
R
1a/KOtBu/
malonate
Product, Yield [%]
able to that of 4a (Table 1, Entry 2), which indicates that
steric factors due to the bulkiness of the nucleophile are not
significant in this reaction.
These observations are further elaborated in Scheme 2.
In accord with our previous work,[7] compound 2a is an
initial product of tele substitution formed by addition of
the malonate carbanion to the electron-deficient ring of 1a
in the 6-position to give intermediate σH adduct 6, which
2[c]
3
4
1[a]
2
Et
Et
tBu
tBu
1:2.5:1.5
1:4.0:3.0
1:2.5:1.5
1:4.0:3.0
2a, 23
3a, 17
4a, 22
4a, 54
4b, 20
4b, 48
[b]
[b]
–
–
3[c]
4
2b[d] Ǟ 5, 26
3b, 18
[b]
[b]
–
–
[a] Unreacted 1 was isolated in 17% yield. [b] Not detected in the
reaction mixture. [c] Unreacted 1 was isolated in 34% yield.
[d] Compound 2b not detected but its hydrolysis during workup
gave 5 in 26% yield.
Scheme 1.
Scheme 2.
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tele Nucleophilic Substitutions of Hydrogen in m-(Trichloromethyl)nitrobenzenes
undergoes elimination of chloride to form exo-dichloro-
methylene cyclohexadiene 7. Intermediate 7 undergoes re-
aromatization through a 1,5-hydrogen shift from the 6-posi-
tion to the exocyclic carbon atom, leading to 6-substituted-
3-(dichloromethyl)benzene 2. Compound 2 further reacts
with the nucleophile to give normal SN2-type substitution
of chloride from the CHCl2 group to give intermediate 8.
The β-elimination of HCl affords α,β-unsaturated double
adduct 3, apparently according to an E1 conjugate-base (E1
cb) mechanism. Compound 3 being an active Michael ac-
ceptor, reacts with the malonate carbanion to yield triple
adduct 4. When a threefold excess of the nucleophile and
Scheme 3.
1a react, mono adduct 2, double adduct 3, and the starting
material were not detected; triple adduct 4 was the only
product. The isolation of aldehyde 5 instead of dichlo-
romethyl derivative 2b (Table 1, Entry 3) might be due to
hydrolysis of the latter due to prolonged exposure to 1 
hydrochloric acid during workup.
spectra showed certain similarities to those reported for
3-(dichloromethylene)-4,6-dimethyl-5-nitrocyclohex-1-ene
isomers.[6] The structures of 11a and 11b were confirmed
1
by H NMR, NOE, and COSY spectroscopy and selective
Support for the first three steps of this mechanism can
be sought in our previous work on tele nucleophilic substi-
tutions.[7] However, the last three steps, that is, conversion
of 2 into 4, may also occur by two consecutive nucleophilic
substitutions of chloride. This is highly unlikely because it
is known that CH acidic centers located in the α-positions
and halogens located in the β-positions with respect to elec-
tron-withdrawing groups undergo facile base-induced β-eli-
mination. This supposition was supported by an experiment
in which 1a was treated with diethyl methylmalonate
(3 equiv.) and KOtBu (4 equiv.) under conditions identical
to those used for the reaction of diethyl malonate and di-
tert-butyl malonate. tele Mono adduct 9 and double adduct
10 resulting from addition of a second equivalent of diethyl
malonate to 9 were obtained in 9 and 56% yield, respec-
tively (Scheme 3). Because elimination of HCl from 10 is
not possible, the formation of the triple adduct was not de-
tected, and as such, it is reasonable to assume that the for-
mation of triple adducts 4a,b (Scheme 2) is the result of
Michael addition of the nucleophile to double adduct 3.
From observations so far regarding the reaction of 1a with
an excess amount of diethyl malonate or di-tert-butyl mal-
onate, the substantial quantity of recovered 1a and the iso-
lation of 3 and 4 as major products indicate that the rates
of further transformation of 2 are higher than the rate of
its formation. Another observation is that in the two-step
reaction involving addition of malonate carbanions to ni-
troarenes 1a,b to produce σH adducts followed by tele elimi-
nation of chloride from the CCl3 group of the σH adducts,
it is the addition step that is rate limiting; hence, the slowest
step of the overall transformation is the addition reaction.
Interestingly, when the reaction of 1a or 1b with diethyl
malonate (3 equiv.) and KOtBu (4 equiv.) was carried out
at –30 °C, different products were formed (Scheme 4) com-
pared to the analogous reaction performed at 0 °C (Table 1,
Entry 2; Scheme 1). Compound 1a gave cyclohexene adduct
11a, double adduct 3a, and triple adduct 4a in 14, 9, and
15% yield, respectively, whereas compound 1b gave cyclo-
decoupling techniques. The hydrogen atoms 1-H and 2-H
of 11a are on the same side of the cyclohexene ring (J1H,2H
= 3.6 Hz), whereas hydrogen atom 3-H is located on the
opposite side (J2H,3H = 10.8 Hz). Similarly for 11b, hydro-
gen atoms 1-H and 2-H (J1H,2H = 3.9 Hz) are located on
the opposite side of hydrogen atom 3-H (J2H,3H = 10.2 Hz).
In the course of these reactions (Scheme 4), we expected
that addition of diethyl potassiomalonate to electrophilic 1a
or 1b proceeds as described in Scheme 2 to give first the
requisite σH adduct, which then undergoes elimination of
chloride to form exo-dichloromethylene cyclohexadiene 12.
Because there are two equal substituents in the 3- and 5-
positions of 11a,b and because only one diastereoisomer
was isolated, protonation of anion 13 must occur with high
diastereoselectivity. It is noteworthy that in the reaction
leading to 11b no side products were detected and the yield
was much higher than that obtained with analog 11a. A
likely explanation stems from the fact that the chlorine
atom at the 1-position of compound 12b forces the exo-
dichloromethylene group to twist out of the plane of the
ring so that 1,5-hydrogen shift is slower than 1,2-addition
to the ring. In the case of 1a where the chlorine atom at the
hexene 11b in 54% yield as the only product. Products 11a
1
and 11b were strikingly nonaromatic, and their H NMR Scheme 4.
Eur. J. Org. Chem. 2010, 3501–3506
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M. Surowiec, D. Belekos, M. Makosza, G. Varvounis
˛
FULL PAPER
1-position is missing, 1,5-hydrogen shift competes with 1,2- initially formed nitrocyclohexadiene adducts was slow, so
addition, which results in a mixture of 11a, 3a, and 4a. that Michael addition of a second carbanion took place to
Furthermore, reactions of 1a and 1b with phenylacetoni- give new, stable cyclohexadiene derivatives. tele-Substitu-
trile and isopropyl phenylacetate were examined tion reactions with carbanions of phenylacetonitrile and
(Scheme 5). The tele substitution reactions proceeded by isopropyl phenylacetate at 0 °C stop when two molecules of
treatment of 1a and 1b each with phenylacetonitrile the carbanion have been added.
(3.0 equiv.) and KOtBu (4 equiv.) in THF/DMF at 0 °C un-
der an atmosphere of argon to give the corresponding α,β-
unsaturated double adducts 14a and 14b in 46 and 37% Experimental Section
yield, respectively. Under similar reaction conditions, tele
substitution of 1b by isopropyl potassiophenylacetate af-
forded α,β-unsaturated double adduct 14c in 44% yield.
General Remarks: Melting points were recorded with a Büchi 510
apparatus and are uncorrected. Infrared spectra were recorded with
a Perkin–Elmer FTIR spectrometer, solids as Nujol mulls and li-
This result offers further confirmation towards the assump-
tion that triple adducts 4a,b in Scheme 2 are products of
nucleophilic addition to α,β-unsaturated double adducts
3a,b. An explanation as to why the reactions shown in
Scheme 5 gave only α,β-unsaturated double adducts 14a–c
even in the presence of nucleophiles derived from phenyl-
acetonitrile and isopropyl phenylacetate, which are stronger
than the nucleophiles derived from diethyl malonate and di-
tert-butyl malonate (Scheme 1), cannot be given.
quids as thin films between sodium chloride discs. NMR spectra
were measured at 400 MHz with a Mercury-400BB or a Bruker
AMX 400 spectrometer, or at 200 MHz with a Gemini-200BB spec-
trometer. Chemical shifts are reported in ppm relative to tetrameth-
ylsilane as internal standard. Mass spectra were obtained by use of
an AMD 604 Inectra GmbH spectrometer in EI or ESI mode. Mass
spectra are given for ions containing 35Cl; appropriate isotope pat-
terns were observed. Flash chromatography was performed at me-
dium pressure by using slurry packed Merck silica gel 230–
400 mesh with the specified eluent. Analytical TLC was carried out
with Merck alufolien sheets Kieselgel 60 F254. Solvents and rea-
gents were used as received from the manufacturers except for THF
and DMF, which were distilled from potassium benzophenone
ketyl and calcium hydride, respectively.
General Procedure for the Treatment of 1-Nitro-3-(trichloromethyl)-
benzene (1a) or 1-Chloro-4-nitro-2-(trichloromethyl)benzene (1b)
with Cyano- and Ester-Stabilized Carbanions: To a stirred solution
of potassium tert-butoxide (2.5 or 4.0 mmol) in tetrahydrofuran
(10 mL) at room temperature, 0, or –30 °C under an atmosphere
of argon was added dropwise a solution of 1a or 1b (1 mmol) and
the appropriate dialkyl malonate, 2-phenylacetonitrile, or isopropyl
2-phenylacetate (1.5 or 3.0 mmol) in DMF (2 mL) over a period of
ca. 1 min. After 3 h, the solution was poured into 1  hydrochloric
acid (100 mL) and extracted with dichloromethane (4ϫ20 mL).
The combined organic extracts were dried (Na2SO4), and the sol-
vent was evaporated under reduced pressure. The resulting crude
residue was purified by flash chromatography (hexane/EtOAc, 1:6)
to afford the corresponding product.
Scheme 5.
Conclusions
We have shown that the reactions of 1-nitro-3-(tri-
chloromethyl)benzene and 1-chloro-4-nitro-2-(trichloro-
methyl)benzene with the potassium salts of the carbanions
of diethyl and di-tert-butyl malonates depend on the stoi-
chiometry of the reagents and the temperature of the reac-
tion. At 0 °C, the carbanions add to the 6-position of the
substrates (ortho to the nitro group and para to the tri-
chloromethyl group) to give anionic σH adducts. Departure
of the chloride ion from the trichloromethyl group of these
adducts followed by re-aromatization through 1,5-hydrogen
shift gives diesters, the result of tele substitution. These di-
esters react with another equivalent of the carbanion pres-
ent in the reaction mixture and replace the halogen in the
dichloromethyl group; this is then followed by elimination
of HCl to give unsaturated tetraesters. The unsaturated
group of these tetraester intermediates is an active Michael
acceptor to a third equivalent of the carbanion, leading to
hexaester derivatives. The use of less than three equivalents
of the carbanion gives mixtures of di-, tetra-, and hexa-
esters. When three equivalents or more of the carbanion
were used, the hexaester was the only product. It should be
noted that when the reaction was carried out at –30 °C with
Diethyl [4-(Dichloromethyl)-2-nitrophenyl]malonate (2a): Yield:
1
11 mg, 3%; yellow oil. H NMR (400 MHz, CDCl3): δ = 8.04 (d,
J = 2.4 Hz, 1 H, 3-H), 7.70 (dd, J = 8.8, 2.4 Hz, 1 H, 5-H), 7.11
(d, J = 8.8 Hz, 1 H, 6-H), 6.70 (s, 1 H, CHCl2), 4.23 (q, J = 7.1 Hz,
4 H, 2 CH2), 3.37 [s, 1 H, CH], 1.30 (t, J = 7.1 Hz, 6 H, 2 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 166.7 (2 C), 153.1 (C),
132.4 (C), 131.7 (C, CH), 123.7 (CH), 114.7 (CH), 69.8 (CH), 65.7
(CH2), 61.5 (CH2), 41.7 (CH), 14.4 (CH3), 14.0 (CH3) ppm. HRMS
(ESI): calcd. for C14H1535Cl2NNaO6 [M + Na]+ 386.0174; found
386.0182. C14H15Cl2NO6 (364.18): calcd. C 46.17, H 4.15, N 3.85;
found C 46.28, H 4.24, N 3.96.
Diethyl {4-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-3-nitrobenzyl-
idene}malonate (3a): Yield: 77 mg, 17%; yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 8.18 (d, J = 1.9 Hz, 1 H, 2-H), 7.71 (dd, J
= 8.2, 1.9 Hz, 1 H, 5-H), 7.70 (s, 1 H, CH=), 7.57 (d, J = 8.2 Hz,
1 H, 6-H), 5.30 (s, 1 H, CH), 4.41–4.23 (m, 8 H, 4 CH2), 1.37–1.21
(m, 12 H, 4 CH3) ppm. 13C NMR (100 MHz, CDCl3) δ = 166.7
(C), 166.5 (C), 165.6 (C), 163.3 (C), 148.8 (C), 135.1 (CH), 134.2
(C), 133.7 (CH), 131.9 (CH), 129.7 (C), 129.5 (C), 125.5 (CH), 62.6
(CH2), 62.2 (CH2), 62.1 (CH2), 62.0 (CH2), 54.3 (CH), 14.0 (CH3),
three equivalents of the carbanion, re-aromatization of the 13.9 (CH3), 13.8 (CH3), 13.7 (CH3) ppm. HRMS (ESI): calcd. for
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tele Nucleophilic Substitutions of Hydrogen in m-(Trichloromethyl)nitrobenzenes
C21H25NNaO10 [M + Na]+ 474.1376; found 474.1417. C21H25NO10
(451.42): calcd. C 55.87, H 5.58, N 3.10; found C 55.83, H 5.43, N
3.17.
130.8, 130.4, 124.1, 69.5, 61.9, 61.7, 59.7, 23.8, 14.2, 14.1 ppm.
HRMS (ESI): calcd. for C15H17Cl2NNaO6 [M + Na]+ 400.0331;
found 400.0347. C15H17Cl2NO6 (378.20): calcd. C 47.64, H 4.53, N
3.70; found C 47.57, H 4.48, N 3.57.
Tetraethyl 2-{4-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-3-nitro-
phenyl}propane-1,1,3,3-tetracarboxylate (4a): Yield: 331 mg, 54%;
(؎)-Diethyl
(Chloro{4-[2-ethoxy-1-(ethoxycarbonyl)-1-methyl-2-
(10): Yield:
colorless microcrystals; m.p. 62–64 °C (EtOH). 1H NMR oxoethyl]-3-nitrophenyl}-methyl)(methyl)malonate
(400 MHz, CDCl3): δ = 8.09 (d, J = 2.0 Hz, 1 H, 2-H), 7.71 (dd, J
= 8.1, 2.0 Hz, 1 H, 5-H), 7.40 (d, J = 8.1 Hz, 1 H, 6-H), 5.22 (s, 1
H, CH), 4.31–4.13 (m, 11 H, 4 CH2, 2 CH, CH), 4.00 (q, J =
7.1 Hz, 4 H, 2 CH2), 1.27 (t, J = 7.1 Hz, 6 H, 2 CH3), 1.23 (t, J =
289 mg, 56%; yellow oil. 1H NMR (200 MHz, CDCl3): δ = 8.12
(d, J = 2.1 Hz, 1 H, 2-H), 7.74 (dd, J = 8.2, 2.1 Hz, 1 H, 6-H), 7.30
(d, J = 8.2 Hz, 1 H, 5-H), 5.85 (s, 1 H, CH), 4.34–4.05 (m, 8 H, 4
CH2), 1.99 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 1.38–1.14 (m, 12 H,
7.1 Hz, 6 H, 2 CH3), 1.05 (t, J = 7.1 Hz, 6 H, 2 CH3) ppm. 13C 4 CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.7 (2 C), 168.6
NMR (100 MHz, CDCl3): δ = 167.4 (2 C), 167.1 (2 C), 166.9 (2 (2 C), 148.4, 138.4, 134.9, 134.2, 129.2, 127.1, 62.6, 62.5, 62.4, 62.2,
C), 148.1 (C), 139.1 (C), 134.9 (CH), 130.8 (CH), 127.4 (C), 126.3
60.9, 59.6, 23.7, 15.1, 14.2 (2 C), 14.0 (2 C) ppm. MS (EI): m/z (%)
(CH), 62.1 (2 CH2), 62.0 (2 CH2), 61.7 (2 CH2), 54.3 (2 CH), 54.2 = 517 (1), 515 (3), 505 (2), 503 (5), 473 (14), 472 (41), 470 (42), 469
(CH), 43.0 (CH), 13.9 (2 CH3), 13.8 (2 CH3), 13.6 (2 CH3) ppm.
MS (EI): m/z (%) = 611 (12.3), 593 (21.1), 566 (32.6), 538 (21.4),
520 (30.9), 502 (25.4), 492 (34.6), 464 (64.4), 446 (72.7), 429 (53.0),
(100), 443 (5), 442 (19), 426 (2), 424 (6). HRMS (ESI): calcd. for
C23H30ClNNaO10 [M
Na]+ 538.1456; found 538.1474.
C23H30ClNO10 (515.94): calcd. C 53.54, H 5.86, N 2.71; found C
+
406 (83.1), 356 (67.8), 260 (100.0). HRMS (ESI): calcd. for 53.66, H 5.99, N 2.59.
C28H37NNaO14 [M + Na]+ 634.2112; found 634.2081. C28H37NO14
(611.59): calcd. C 54.99, H 6.10, N, 2.29; found C 55.08, H 6.17,
N 2.32.
(؎)-Tetraethyl 2,2Ј-[6-(Dichloromethylene)-2-nitrocyclohex-4-ene-
1,3-diyl]dimalonate (11a): Yield: 74 mg, 14%; orange oil. 1H NMR
(400 MHz, CDCl3): δ = 6.41 (d, J = 10.4, Hz, 1 H, 5-H), 5.94 (dd,
Di-tert-butyl {4-[2-tert-Butoxy-1-(tert-butoxycarbonyl)-2-oxoethyl]- J = 10.4, 2.4 Hz, 1 H, 4-H), 4.96 (dd, J = 10.8, 3.6 Hz, 1 H, 2-H),
3-nitrobenzylidene}malonate (3b): Yield: 102 mg, 18%; yellow oil. 4.64 (dd, J = 8.8, 3.6 Hz, 1 H, 1-H), 4.27–3.94 (m, 8 H, 4 CH2),
1H NMR (200 MHz, CDCl3): δ = 8.20 (d, J = 1.9 Hz, 1 H, 2-H), 3.74 (d, J = 8.8 Hz, 1 H, CH), 3.33 (d, J = 2.8 Hz, 1 H, CH), 1.28–
7.71 (dd, J = 8.4, 1.9 Hz, 1 H, 6-H), 7.57 (d, J = 8.4 Hz, 1 H, 5-
H), 7.50 (s, 1 H, CH=), 5.10 (s, 1 H, CH), 1.48 (s, 18 H, 6 CH3),
1.38 (s, 18 H, 6 CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 167.1
1.10 (m, 12 H, 4 CH3) ppm. 13C NMR (100 MHz, CDCl3) δ =
167.6 (C), 167.1 (C), 166.8 (C), 166.7 (C), 130.0 (C), 128.2 (CH),
125.0 (CH), 123.2 (C), 85.0 (CH), 62.9 (CH2), 62.7 (CH2), 62.6
(2 C), 163.0 (2 C), 149.3 (C), 138.0 (C), 136.3 (CH), 134.5 (C), (CH2), 62.5 (CH2), 51.3 (CH), 50.9 (CH), 40.5 (CH), 36.8 (CH),
134.0 (CH), 132.1 (C), 131.6 (CH), 125.2 (CH), 83.6 (2 C), 83.3 (2 14.5 (CH3), 14.4 (CH3), 14.3 (CH3), 14.2 (CH3) ppm. HRMS (ESI):
C), 56.5 (CH), 28.3 (6 CH3), 28.0 (6 CH3) ppm. HRMS (ESI):
calcd. for C29H41NNaO10 [M + Na]+ 586.2628; found 586.2657.
C29H41NO10 (563.63): calcd. C 61.80, H 7.33, N 2.49; found C
61.76, H 7.39, N 2.56.
calcd. for C21H2735Cl2NNaO10 [M Na]+ 546.0910; found
+
546.0895. C21H27Cl2NO10 (524.34): calcd. C 48.10, H 5.19, N 2.67;
found C 48.01, H 5.23, N 2.71.
(؎)-Tetraethyl
2,2Ј-[5-Chloro-6-(dichloromethylene)-2-nitrocyclo-
Tetra-tert-butyl 2-{4-[2-tert-Butoxy-1-(tert-butoxycarbonyl)-2-oxo- hex-4-ene-1,3-diyl]dimalonate (11b): Yield: 302 mg, 54%; orange
1
ethyl]-3-nitrophenyl}prop-1-ene-1,1,3,3-tetracarboxylate (4b): Yield:
375 mg, 48%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.10 H), 5.17 (dd, J = 10.2, 3.9 Hz, 1 H, 2-H), 4.88 (dd, J = 9.8, 3.9 Hz,
(d, J = 1.9 Hz, 1 H, 2-H), 7.65 (dd, J = 8.2, 2.0 Hz, 1 H, 6-H), 7.43 1 H, 1-H), 4.28–4.10 (m, 8 H, 4 CH2), 3.95 (ddd, J = 10.2, 3.9,
(d, J = 8.2 Hz, 1 H, 5-H), 5.01 (s, 1 H, CH), 4.18–3.80 (m, 3 H, 3 3.2 Hz, 1 H, 3-H), 3.83 (d, J = 9.8 Hz, 1 H, CH), 3.45 (d, J =
CH), 1.46 (s, 18 H, 6 CH3), 1.40 (s, 18 H, 6 CH3), 1.26 (s, 18 H, 6
3.2 Hz, 1 H, CH), 1.34–1.22 (m, 12 H, 4 CH3) ppm. 13C NMR
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.2 (2 C), 167.0 (100 MHz, CDCl3) δ = 167.2 (C), 166.6 (C), 166.3 (C), 166.2 (C),
oil. H NMR (400 MHz, CDCl3): δ = 6.25 (d, J = 3.9 Hz, 1 H, 4-
(2 C), 166.4 (2 C), 148.6 (C), 139.6 (C), 135.5 (CH), 130.6 (CH),
128.0 (C), 127.0 (C), 82.7 (2 C), 82.5 (2 C), 82.3 (2 C), 56.4 (CH),
129.4 (CH), 127.8 (2 C), 127.2 (C), 83.7 (CH), 62.8 (CH2), 62.7
(CH2), 62.6 (CH2), 62.5 (CH2), 51.8 (CH), 50.4 (CH), 44.3 (CH),
56.3 (2 CH), 43.3 (CH), 28.1 (6 CH3), 28.0 (6 CH3), 27.8 (6 CH3) 38.5 (CH), 14.3 (CH3), 14.2 (CH3), 14.1 (CH3), 14.0 (CH3) ppm.
ppm. HRMS (ESI): calcd. for C40H61NNaO14 [M + Na]+ 802.3990; HRMS (ESI): calcd. for C21H2635Cl3NNaO10 [M + Na]+ 580.0520;
found 802.4100. C40H61NO14 (779.91): calcd. C 61.60, H 7.88, N
1.80; found C 61.56, H 7.76, N 1.74.
found 580.0545. C21H26Cl3NO10 (558.79): calcd. C 45.14, H 4.69,
N 2.51; found C 45.03, H 4.79, N 2.46.
Di-tert-Butyl (4-Formyl-2-nitrophenyl)malonate (5): Yield: 95 mg, (؎)-(2E)-3-{4-[Cyano(phenyl)methyl]-3-nitrophenyl}-2-phenylacrylo-
1
26%; yellow oil. H NMR (200 MHz, CDCl3): δ = 10.09 (s, 1 H, nitrile (14a): Yield: 169 mg, 46%; colorless microcrystals; m.p. 125–
CHO), 8.51 (d, J = 1.6 Hz, 1 H, 3-H), 8.14 (dd, J = 8.0, 1.6 Hz, 1
H, 5-H), 7.78 (d, J = 8.0 Hz, 1 H, 6-H), 5.17 (s, 1 H, CH), 1.50 (s,
126 °C (EtOH). 1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J =
2.0 Hz, 1 H, 2-H), 8.27 (dd, J = 8.2, 2.0 Hz, 1 H, 6-H), 7.83 (d, J
18 H, 6 CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 189.6 (CH), = 8.2 Hz, 1 H, 5-H), 7.73–7.67 (m, 2 H, Ph), 7.54 (s, 1 H, CH=),
166.0 (2 C), 149.8 (C), 136.7 (C), 134.9 (C), 133.1 (CH), 132.5 7.52–7.45 (m, 3 H, Ph), 7.43–7.33 (m, 5 H, Ph), 6.18 (s, 1 H, CH)
(CH), 126.1 (CH), 83.7 (2 C), 56.7 (CH), 28.1 (6 CH3) ppm. HRMS
(ESI): calcd. for C18H23NNaO7 [M + Na]+ 388.1372; found
388.1384. C18H12NO7 (365.38): calcd. C 59.17, H 6.34, N 3.83;
found C 59.11, H 6.29, N 3.71.
ppm. 13C NMR (100 MHz, CDCl3): δ = 147.8 (C), 137.4 (CH),
135.5 (C), 133.5 (C), 133.4 (CH), 133.1 (C), 131.7 (C), 131.6 (CH),
130.3 (CH), 129.5 (CH), 129.3 (CH), 128.9 (2 CH), 127.9 (2 CH),
126.4 (2 CH), 126.2 (2 CH), 118.2 (C), 116.8 (C), 116.1 (C), 38.3
(CH) ppm. HRMS (ESI): calcd. for C23H15N3NaO2 [M + Na]+
388.1062; found 388.1076.. C23H15N3O2 (365.38): calcd. C 75.60,
H 4.14, N 11.50; found C 75.51, H 4.16, N 11.42.
Diethyl [4-(Dichloromethyl)-2-nitrophenyl](methyl)malonate (9):
Yield: 35 mg, 9%; yellow oil. 1H NMR (200 MHz, CDCl3): δ =
8.23 (d, J = 2.1 Hz, 1 H, 3-H), 7.83 (dd, J = 8.4, 2.1 Hz, 1 H, 5-
H), 7.44 (d, J = 8.4 Hz, 1 H, 6-H), 6.77 (s, 1 H, CH), 4.64–4.22 (؎)-(2E)-3-{2-Chloro-4-[cyano(phenyl)methyl]-5-nitrophenyl}-2-phen-
(m, 4 H, 2 CH2), 2.03 (s, 3 H, CH3), 1.35–1.20 (m, 6 H, 2 CH3)
ylacrylonitrile (14b): Yield: 149 mg, 37%; yellow oil. 1H NMR
(200 MHz, CDCl3): δ = 8.85 (s, 1 H, 6-H), 7.86 (s, 1 H, 5-H), 7.79
ppm. 13C NMR (50 MHz, CDCl3): δ = 169.5, 141.1, 136.3, 134.5,
Eur. J. Org. Chem. 2010, 3501–3506
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3505

M. Surowiec, D. Belekos, M. Makosza, G. Varvounis
˛
FULL PAPER
[2]
a) O. N. Chupakhin, V. N. Charushin, H. C. van der Plas, Nu-
cleophilic Aromatic Substitution of Hydrogen, Academic Press,
(s, 1 H, CH=), 7.79–7.72 (m, 2 H, Ph), 7.56–7.50 (m, 3 H, Ph),
7.44–7.34 (m, 5 H, Ph), 6.26 (s, 1 H, CH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 146.1 (C), 140.6 (C), 134.6 (C), 134.3 (CH), 133.3 (C),
133.2 (CH), 132.9 (C), 132.3 (C), 131.0 (CH), 129.9 (CH), 129.7
(CH), 129.5 (2 CH), 128.2 (2 CH), 126.9 (2 CH), 126.8 (2 CH),
118.9 (C), 118.1 (C), 116.4 (C), 38.4 (CH) ppm. C23H14ClN3O2
(399.83): calcd. C 69.09, H 3.53, N 10.51; found C 69.06, H 3.46,
N 10.50.
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˛
491–504; c) M. Makosza, J. Wojciechowski, Chem. Rev. 2004,
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a) M. Ma˛kosza, M. Paszewski, Pol. J. Chem. 2005, 79, 163–
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(؎)-Isopropyl
(2E)-3-[2-Chloro-4-(2-isopropoxy-2-oxo-1-phenyl-
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ethyl)-5-nitrophenyl]-2-phenylacrylate (14c): Yield: 215 mg, 44%;
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1
Mayr, Chem. Eur. J. 2008, 14, 6108–6118; d) M. Achmatowicz,
O. R. Thiel, G. Gorins, C. Goldstein, C. Affouard, R. Jensen,
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yellow oil. H NMR (200 MHz, CDCl3): δ = 7.73 (s, 1 H, CH=),
7.72 (d, J = 1.9 Hz, 1 H, 2-H), 7.43–7.30 (m, 7 H, Ph), 7.25–7.18
(m, 3 H, Ph), 7.11 (dd, J = 8.3, 1.9 Hz, 1 H, 6-H), 6.87 (d, J =
8.3 Hz, 1 H, 5-H), 5.53 (s, 1 H, CH), 5.24–5.00 (m, 2 H, CH), 1.31
(d, J = 6.4 Hz, 12 H, 4 CH3) ppm. 13C NMR (50 MHz, CDCl3): δ
= 170.8 (2 C), 148.9 (C), 136.6 (C), 136.4 (CH), 136.3 (C), 135.4
(C), 135.1 (2 C), 134.4 (CH), 131.6 (CH), 129.6 (CH), 129.4 (CH),
129.3 (CH), 129.1 (2 CH), 128.6 (2 CH), 128.1 (2 CH), 126.8 (2
CH), 69.5 (CH), 69.3 (CH), 53.6 (CH), 22.0 (CH3), 21.9 (CH3),
21.6 (2 CH3) ppm. C29H28ClNO6 (521.99): calcd. C 66.73, H 5.41,
N, 2.68; found C 66.65, H 5.34, N 2.59.
´
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Acknowledgments
The work in Warsaw was financially supported by the State Com-
mittee for Scientific Research (grant no. PBZ 6.01). The work in
Greece was financially supported by a Joint Research and Technol-
ogy Program between Greece and Poland from the General Secre-
tariat of Science and Technology, Athens (grant no. 2013555).
2000, 56, 447–453; d) M. Makosza, G. Varvounis, M. Surowiec,
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[1] a) J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Am-
sterdam, 1968 ; b) F. Terrier, Nucleophilic Aromatic Displace-
ment, Verlag Chemie Weinheim, 1991.
T. Giannopoulos, Eur. J. Org. Chem. 2003, 3791–3799.
Received: November 14, 2009
Published Online: May 12, 2010
3506
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3501–3506